Abstract. Water infrastructure development is considered necessary to drive economic growth in the Mekong region of mainland Southeast Asia. Yet the current understanding of hydrological and flood pattern changes associated with infrastructural development still contains several knowledge gaps, such as the interactions between multiple drivers, which may have serious implications for water management, agricultural production, and ecosystem services. This research attempts to conduct a cumulative assessment of basin-wide hydropower dam construction and irrigation expansion, as well as climate change, implications on discharge, and flood changes in the Cambodian Mekong floodplain. These floodplains offer important livelihoods for a considerable part of the 6.4 million people living on them, as they are among the most productive ecosystems in the world – driven by the annual flood pulse. To assess the potential future impacts, we used an innovative combination of three models: Mekong basin-wide distributed hydrological model IWRM-VMod, with the Mekong delta 1D flood propagation model MIKE-11 and 2D flood duration and extent model IWRM-Sub enabling detail floodplain modelling. We then ran scenarios to approximate possible conditions expected by around 2050. Our results show that the monthly and seasonal hydrological regimes (discharges, water levels, and flood dynamics) will be subject to substantial alterations under future development scenarios. Projected climate change impacts are expected to decrease dry season flows and increase wet season flows, which is in opposition to the expected alterations under development scenarios that consider both hydropower and irrigation. The likely impact of decreasing water discharge in the early wet season (up to −30 %) will pose a critical challenge to rice production, whereas the likely increase in water discharge in the mid-dry season (up to +140 %) indicates improved water availability for coping with drought stresses and sustaining environmental flows. At the same time, these changes would have drastic impacts on total flood extent, which is projected to decline by around 20 %, having potentially negative impacts on floodplain productivity and aquaculture, whilst reducing the flood risk to more densely populated areas. Our findings demonstrate the substantial changes that planned infrastructural development will have on the area, potentially impacting important ecosystems and people's livelihoods, calling for actions to mitigate these changes as well as planning potential adaptation strategies.